Beneficial Uses of Arsenic

INTRODUCTION

Recently an important article came out (abstract given
below) which argues that moderate to high doses of arsenic given for a
period of 30 days can cure leukemia. It is important to realize that
this is not in contradiction to the evidence that arsenic given at low
doses for 15 years or more can produce high cancer rates (i.e.. kidney,
bladder, lung).

The doses given for curative purposes were for about
30 days and the accumulated doses were about 300 mg. By way
of comparison a person drinking 2 liters of water a day for 20 years
with 500 µg/litre of arsenic (as was the case in Chile) will
accumulate 7500 mg - 20 times more. So if the accumalated dose is
the criterion for developing cancer, as is strongly believed, there should
be no problem with the doses given for curative purposes.

Background.
Two reports from China have suggested that arsenic trioxide can induce
complete remissions in patients with acute promyelocytic leukemia
(APL). We evaluated this drug in patients with APL in an attempt to elucidate
its mechanism of action.

Methods.
Twelve patients with APL who had relapsed after extensive prior therapy
were treated with arsenic trioxide at doses ranging from 0.06 to
0.2 mg per kilogram of body weight per day until visible leukemic cells
were eliminated from the bone marrow. Bone marrow mononuclear cells were
serially monitored by flow cytometry for immunophenotype, fluorescence
in situ hybridization reverse-transcription-polymerase-chain-reaction (RT-PCR)
assay for PML-RAR-(alpha) fusion transcripts, and Western blot analysis
for expression of the apoptosis-associated proteins caspases 1, 2, and
3.

Results.
Of the 12 patients studied, 11 had a complete remission after treatment
that lasted from 12 to 39 days (range of cumulative doses, 160 to
515 mg). Adverse effects were relatively mild and included rash, lightheadedness,
fatigue, and musculoskeletal pain. Cells that expressed both CD11b and
CD33 (antigens characteristic of mature and immature cells, respectively),
and which were found by fluorescence in situ hybridization to carry the
t(15;17) translocation, increased progressively in number during treatment
and persisted in the early phase of complete remission. Eight of
11 patients who initially tested positive for the PML-RAR-(alpha) fusion
transcript by the RT-PCR assay later tested negative; 3 other patients,
who persistently tested positive, relapsed early. Arsenic trioxide
induced the expression of the proenzymes of caspase 2 and caspase
3 and activation of both caspase 1 and caspase 3.

Conclusions.
Low doses of arsenic trioxide can induce complete remissions in patients
with APL who have relapsed. The clinical response is associated with incomplete
cytodifferentiation and the induction of apoptosis with caspase activation
in leukemic cells. (N Engl J Med 1998;339:1341-8.)

From the Developmental Chemotherapy Service (S.L.S., L.J.D., R.P.W.)
and the Leukemia Service (P.M., A.D., J.G., D.A.S.), Department of Medicine;
the Departments of Human Genetics (Z.-G.W., S.J., P.P.P.) and Pediatrics
(E.C.); and the Division of Pharmacy (D.C.) -- all at Memorial Sloan-Kettering
Cancer Center and the Cornell University Medical College, New York.
Address reprint requests to Dr. Warrell at the Memorial Sloan-Kettering
Cancer Center, 1275 York Ave., New York, NY 10021.

The idea
that high doses can destroy a tumor, whereas continuous low doses can create
a tunor is not new. For example radiotherapy cures cancer by destroying
a tumor but at the same time there is also a small (about 5%) chance of
a secondary tumor developing later.

Article on the same topic as the above NEJM article
translated from the French.

Arsenic, well known as a poison, can specifically target
the product of a genetic lesion behind a specific type of leukemia... This
is the paradoxical result that has just been reached by co-operation between
a Chinese team from the Shanghai Institute of Hematology, and a French
team from the "Cellular pathology: molecular and viral aspects" laboratory
of the CNRS, led by Professor Hugues de Thé. Acute promyelocytic
leukemia (a rare type of blood cancer) is specifically associated with
a chromosome translocation which creates an oncogenic abnormal protein,
PML/RARa, resulting from fusion between two genes: PML and RARa. This leukemia
is currently well treated by retinoic acid (a hormone which binds RARa)
in combination with chemotherapy, providing the first example of oncogene-targeted
therapy. Recently, Chinese teams have shown that arsenic has a therapeutic
effect on patients suffering from this type of leukemia. Unlike retinoic
acid, which triggers cell differentiation, arsenic induces programmed death,
or apoptosis. This Franco-Chinese co-operation examined the mode of action
of arsenic and showed that, like retinoic acid, arsenic causes the oncogene
PML/RARa to be degraded, highlighting a surprising similitude between the
effects of the two agents. While retinoic acid acts on the RAR portion
of the fusion, arsenic acts on its PML portion. This data can be used to
propose a physio-pathological model of this disease in which RAR would
control differentiation while PML would control apoptosis. Arsenic even
acts in patients showing clinical resistance to retinoids, suggesting that
combined treatments could be envisaged.